Combined remodeling control therapy and anti-remodeling therapy by implantable cardiac device

ABSTRACT

A method and device for delivering ventricular resynchronization pacing therapy in conjunction with electrical stimulation of nerves which alter the activity of the autonomic nervous system is disclosed. Such therapies may be delivered by an implantable device and are useful in preventing the deleterious ventricular remodeling which occurs as a result of a heart attack or heart failure. The device may perform an assessment of cardiac function in order to individually modulate the delivery of the two types of therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/850,341, filed on May 20, 2004, now issued as U.S. Pat. No.7,260,431, the specification of which is incorporated herein byreference.

This patent application is related to co-pending and commonly assignedU.S. patent application Ser. No. 10/700,368 filed Nov. 3, 2003, thedisclosures of which are incorporated by reference.

FIELD OF THE INVENTION

This patent application pertains to methods and apparatus for thetreatment of cardiac disease. In particular, it relates to methods andapparatus for improving cardiac function with electro-stimulatorytherapy.

BACKGROUND

Following myocardial infarction (MI) or other cause of decreased cardiacoutput, a complex remodeling process of the ventricles occurs thatinvolves structural, biochemical, neurohormonal, and electrophysiologicfactors. Ventricular remodeling is triggered by a physiologicalcompensatory mechanism that acts to increase cardiac output due toso-called backward failure which increases the diastolic fillingpressure of the ventricles and thereby increases the so-called preload(i.e., the degree to which the ventricles are stretched by the volume ofblood in the ventricles at the end of diastole). An increase in preloadcauses an increase in stroke volume during systole, a phenomena known asthe Frank-Starling principle. When the ventricles are stretched due tothe increased preload over a period of time, however, the ventriclesbecome dilated. The enlargement of the ventricular volume causesincreased ventricular wall stress at a given systolic pressure. Alongwith the increased pressure-volume work done by the ventricle, this actsas a stimulus for hypertrophy of the ventricular myocardium. Thedisadvantage of dilatation is the extra workload imposed on normal,residual myocardium and the increase in wall tension (Laplace's Law)which represent the stimulus for hypertrophy. If hypertrophy is notadequate to match increased tension, a vicious cycle ensues which causesfurther and progressive dilatation.

As the heart begins to dilate, afferent baroreceptor and cardiopulmonaryreceptor signals are sent to the vasomotor central nervous systemcontrol center, which responds with hormonal secretion and sympatheticdischarge. It is the combination of hemodynamic, sympathetic nervoussystem and hormonal alterations (such as presence or absence ofangiotensin converting enzyme (ACE) activity) that ultimately accountfor the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction.

It has been shown that the extent of ventricular remodeling ispositively correlated with increased mortality in post-MI and heartfailure patients. It is with reversing and/or preventing suchventricular remodeling that the present invention is primarilyconcerned.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the physical placement of an implantable cardiacdevice.

FIG. 2 is a system diagram of a cardiac device configured for multi-sitestimulation and sensing.

FIG. 3 illustrates an embodiment of an implantable device withRF-controlled satellite units for neural stimulation.

FIGS. 4A-D illustrate examples of how the intensities of ART and RCT maybe individually time-varied.

DETAILED DESCRIPTION

Clinical data has shown that cardiac resynchronization therapy (CRT),achieved through synchronized biventricular pacing, results in asignificant improvement in cardiac function. It has also been reportedCRT can be beneficial in preventing and/or reversing the ventricularremodeling that often occurs in post-MI and heart failure patients. Asexplained in detail below, the present invention relates to animplantable cardiac device capable of providing remodeling controltherapy (RCT) by controlling ventricular activation with cardiacresynchronization pacing and providing anti-remodeling therapy (ART) bystimulating the baroreflex in order to inhibit sympathetic activity. Thecombined application of these two therapies provides a greatertherapeutic benefit than either of them individually. The devicecontrols ventricular activation through synchronized pacing of the rightand left ventricles. In addition, the device may provide a combinationof parasympathetic stimulation and sympathetic inhibition.Parasympathetic stimulation can be achieved through a nerve cuffelectrode placed around the cervical vagus nerve bundle, whilesympathetic inhibition can be achieved through baroreflex stimulation,either through a nerve cuff electrode placed around the aortic orcarotid sinus nerve, or though a stimulation lead designed to stimulatebaroreceptors in the pulmonary artery. The device controls the deliveryof RCT and ART independently in either an open-loop or closed-loopfashion, the latter based upon a cardiac function assessment performedby the device.

1. Remodeling Control Therapy by Cardiac Resynchronization Pacing

Implantable cardiac devices that provide electrical stimulation toselected chambers of the heart have been developed in order to treat anumber of cardiac disorders. A pacemaker, for example, is a device whichpaces the heart with timed pacing pulses, most commonly for thetreatment of bradycardia where the ventricular rate is too slow.Atrio-ventricular conduction defects (i.e., AV block) and sick sinussyndrome represent the most common causes of bradycardia for whichpermanent pacing may be indicated. If functioning properly, thepacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Implantable devices may also be used to treatcardiac rhythms that are too fast, with either anti-tachycardia pacingor the delivery of electrical shocks to terminate atrial or ventricularfibrillation.

Implantable devices have also been developed that affect the manner anddegree to which the heart chambers contract during a cardiac cycle inorder to promote the efficient pumping of blood. The heart pumps moreeffectively when the chambers contract in a coordinated manner, a resultnormally provided by the specialized conduction pathways in both theatria and the ventricles that enable the rapid conduction of excitation(i.e., depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Pathology of these conduction pathways and otherinter-ventricular or intra-ventricular conduction deficits can be acausative factor in heart failure, which refers to a clinical syndromein which an abnormality of cardiac function causes cardiac output tofall below a level adequate to meet the metabolic demand of peripheraltissues. In order to treat these problems, implantable cardiac deviceshave been developed that provide appropriately timed electricalstimulation to one or more heart chambers in an attempt to improve thecoordination of atrial and/or ventricular contractions, termed cardiacresynchronization therapy (CRT). Ventricular resynchronization is usefulin treating heart failure because, although not directly inotropic,resynchronization can result in a more coordinated contraction of theventricles with improved pumping efficiency and increased cardiacoutput. Currently, a most common form of CRT applies stimulation pulsesto both ventricles, either simultaneously or separated by a specifiedbiventricular offset interval, and after a specified atrio-ventriculardelay interval with respect to the detection of an intrinsic atrialcontraction or delivery of an atrial pace.

It has also been found that CRT can be beneficial in reducing thedeleterious ventricular remodeling which can occur in post-MI and heartfailure patients. Presumably, this occurs as a result of changes in thedistribution of wall stress experienced by the ventricles during thecardiac pumping cycle when CRT is applied. The degree to which a heartmuscle fiber is stretched before it contracts is termed the preload, andthe maximum tension and velocity of shortening of a muscle fiberincreases with increasing preload. When a myocardial region contractslate relative to other regions, the contraction of those opposingregions stretches the later contracting region and increases thepreload. The degree of tension or stress on a heart muscle fiber as itcontracts is termed the afterload. Because pressure within theventricles rises rapidly from a diastolic to a systolic value as bloodis pumped out into the aorta and pulmonary arteries, the part of theventricle that first contracts due to an excitatory stimulation pulsedoes so against a lower afterload than does a part of the ventriclecontracting later. Thus a myocardial region which contracts later thanother regions is subjected to both an increased preload and afterload.This situation is created frequently by the ventricular conductiondelays associated with heart failure and ventricular dysfunction due toan MI. The increased wall stress to the late-activating myocardialregions is most probably the trigger for ventricular remodeling. Bypacing one or more sites in a ventricle in a manner which causes a morecoordinated contraction, CRT provides pre-excitation of myocardialregions which would otherwise be activated later during systole andexperience increased wall stress. The pre-excitation of the remodeledregion relative to other regions unloads the region from mechanicalstress and allows reversal or prevention of remodeling to occur.

2. Anti-Remodeling Therapy by Modulating Autonomic Activity

As noted above, activity of the autonomic nervous system is at leastpartly responsible for the ventricular remodeling which occurs as aconsequence of an MI or due to heart failure. It has been demonstratedthat remodeling can be affected by pharmacological intervention with theuse of, for example, ACE inhibitors and beta-blockers. Pharmacologicaltreatment carries with it the risk of side effects, however, and it isalso difficult to modulate the effects of drugs in a precise manner. Inaccordance with the present invention, electrostimulatory means areemployed to modulate autonomic activity, referred to as anti-remodelingtherapy or ART. When delivered in conjunction with ventricularresynchronization pacing, such modulation of autonomic activity actssynergistically to reverse or prevent cardiac remodeling.

3. Exemplary Device Description

As shown in FIG. 1, an implantable cardiac device 100 for delivering CRTis typically placed subcutaneously or submuscularly in a patient's chestwith leads 200 threaded intravenously into the heart to connect thedevice to electrodes 300 used for sensing and pacing of the atria and/orventricles. Electrodes may also be positioned on the epicardium byvarious means. A programmable electronic controller causes the pacingpulses to be output in response to lapsed time intervals and sensedelectrical activity (i.e., intrinsic heart beats not as a result of apacing pulse). The device senses intrinsic cardiac electrical activitythrough a sensing channel which incorporates internal electrodesdisposed near the chamber to be sensed. A depolarization wave associatedwith an intrinsic contraction of the atria or ventricles that isdetected by the device is referred to as an atrial sense or ventricularsense, respectively. In order to cause such a contraction in the absenceof an intrinsic beat, a pacing pulse with energy above a certainthreshold is delivered to the chamber through a pacing channel whichincorporates internal electrodes disposed near the chamber to be paced.Also shown in the figure is a satellite unit 110 which incorporateselectrodes for neural stimulation and which communicates with the device100 via a wireless link.

FIG. 2 shows a system diagram of an exemplary microprocessor-basedcardiac device. The device is equipped with multiple sensing and pacingchannels which may be physically configured to sense and/or pacemultiple sites in the atria or the ventricles. The device shown in FIG.1 can be configured for cardiac resynchronization pacing of the atria orventricles. The multiple sensing/pacing channels may be configured, forexample, with one atrial and two ventricular sensing/pacing channels fordelivering biventricular resynchronization therapy, with the atrialsensing/pacing channel used to deliver the biventricularresynchronization therapy in an atrial tracking mode as well as to pacethe atria if required. The controller 10 of the device is amicroprocessor which communicates with a memory 12 via a bidirectionaldata bus. The controller could be implemented by other types of logiccircuitry (e.g., discrete components or programmable logic arrays) usinga state machine type of design, but a microprocessor-based system ispreferable. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor.

Shown in the FIG. 2 are three exemplary sensing and pacing channelsdesignated “a” through “c” comprising bipolar leads with ring electrodes34 a-c and tip electrodes 33 a-c, sensing amplifiers 31 a-c, pulsegenerators 32 a-c, and channel interfaces 30 a-c. Each channel thusincludes a pacing channel made up of the pulse generator connected tothe electrode and a sensing channel made up of the sense amplifierconnected to the electrode. The channel interfaces 30 a-c communicatebidirectionally with microprocessor 10, and each interface may includeanalog-to-digital converters for digitizing sensing signal inputs fromthe sensing amplifiers and registers that can be written to by themicroprocessor in order to output pacing pulses, change the pacing pulseamplitude, and adjust the gain and threshold values for the sensingamplifiers. The sensing circuitry of the pacemaker detects a chambersense, either an atrial sense or ventricular sense, when an electrogramsignal (i.e., a voltage sensed by an electrode representing cardiacelectrical activity) generated by a particular channel exceeds aspecified detection threshold. Pacing algorithms used in particularpacing modes employ such senses to trigger or inhibit pacing, and theintrinsic atrial and/or ventricular rates can be detected by measuringthe time intervals between atrial and ventricular senses, respectively.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a MOS switching network 70 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing or can 80 serving as a ground electrode. A shock pulsegenerator 60 is also interfaced to the controller for delivering adefibrillation shock via a pair of shock electrodes 61 to the atria orventricles upon detection of a shockable tachyarrhythmia.

The controller 10 controls the overall operation of the device inaccordance with programmed instructions stored in memory, includingcontrolling the delivery of paces via the pacing channels, interpretingsense signals received from the sensing channels, and implementingtimers for defining escape intervals and sensory refractory periods. Thecontroller is capable of operating the device in a number of programmedpacing modes which define how pulses are output in response to sensedevents and expiration of time intervals. Most pacemakers for treatingbradycardia are programmed to operate synchronously in a so-calleddemand mode where sensed cardiac events occurring within a definedinterval either trigger or inhibit a pacing pulse. Inhibited demandpacing modes utilize escape intervals to control pacing in accordancewith sensed intrinsic activity such that a pacing pulse is delivered toa heart chamber during a cardiac cycle only after expiration of adefined escape interval during which no intrinsic beat by the chamber isdetected. Escape intervals for ventricular pacing can be restarted byventricular or atrial events, the latter allowing the pacing to trackintrinsic atrial beats. CRT is most conveniently delivered inconjunction with a bradycardia pacing mode where, for example, multipleexcitatory stimulation pulses are delivered to multiple sites during acardiac cycle in order to both pace the heart in accordance with abradycardia mode and provide pre-excitation of selected sites. Anexertion level sensor 330 (e.g., an accelerometer, a minute ventilationsensor, or other sensor that measures a parameter related to metabolicdemand) enables the controller to adapt the pacing rate in accordancewith changes in the patient's physical activity and, as explained below,can enable the controller to modulate the delivery of neural stimulationand/or cardiac resynchronization pacing. A telemetry interface 40 isalso provided which enables the controller to communicate with anexternal programmer or remote monitor.

Neural stimulation channels are incorporated into the device fordelivering parasympathetic stimulation and/or sympathetic inhibition,where one channel includes a bipolar lead with a ring electrode 44 and atip electrode 43, a pulse generator 42, and a channel interface 40, andthe other channel includes a bipolar lead with a ring electrode 54 and atip electrode 53, a pulse generator 52, and a channel interface 50.Other embodiments may use unipolar leads in which case the neuralstimulation pulses are referenced to the can or another electrode. Thepulse generator for each channel outputs a train of neural stimulationpulses which may be varied by the controller as to amplitude, frequency,and duty-cycle. In this embodiment, each of the neural stimulationchannels uses a lead which can be intravascularly disposed near anappropriate stimulation site, e.g., near a baroreceptor in the case of asympathetic inhibition channel or near a parasympathetic nerve in thecase of a parasympathetic stimulation channel. Other types of leadsand/or electrodes may also be employed. A nerve cuff electrode may beused in place of an intravascularly disposed electrode to provide neuralstimulation, where the electrode may be placed, for example, around thecervical vagus nerve bundle to provide parasympathetic stimulation oraround the aortic or carotid sinus nerve to provide sympatheticinhibition. In another embodiment, the leads of the neural stimulationelectrodes are replaced by wireless links, and the electrodes forproviding parasympathetic stimulation and/or sympathetic inhibition areincorporated into satellite units. The wireless link may be, forexample, a radio-frequency (RF) link or an acoustic link. FIG. 1illustrates this wireless embodiment where the implantable device 100communicates with such a satellite unit 110 via a wireless transmitterinterfaced to the controller. The satellite unit 110 is an integratedassembly adapted for surgical implantation which includes a housingcontaining a battery and circuitry for outputting neural stimulationpulses to an external electrode which can clip around a target nerve(e.g., vagus, carotid sinus, or aortic nerve). FIG. 3 illustrates thefunctional components of the implantable device 100 and satellite unit110 relevant to this embodiment. The implantable device includes awireless transmitter 101 (e.g., either an RF transmitter or an acoustictransducer) interfaced to the controller 10 for transmitting commands,and the satellite unit 110 includes a wireless receiver 111 (e.g.,either an RF receiver or a microphone for receiving acoustic signals)interfaced to control circuitry 112 for receiving the commands. Thecontrol circuitry 112 translates the received commands and causes pulsegeneration circuitry 113 to output appropriate stimulation pulses to theexternal electrode 120.

4. Assessment of Cardiac Function

In one embodiment of the invention, the delivery of RCT and/or ART ismodulated in accordance with an assessment of cardiac function performedby the implantable device. One means by which cardiac function may beassessed is by measuring cardiac output and comparing it with thepatient's measured exertion level. Cardiac output may be measured by animpedance technique in which transthoracic impedance is measured andused compute stroke volume. In one embodiment, the exertion level sensoris a minute ventilation sensor which includes an exciter and animpedance measuring circuit. The exciter supplies excitation current ofa specified amplitude (e.g., as a pulse waveform with constantamplitude) to excitation electrodes that are disposed in the thorax.Voltage sense electrodes are disposed in a selected region of the thoraxso that the potential difference between the electrodes while excitationcurrent is supplied is representative of the transthoracic impedancebetween the voltage sense electrodes. The conductive housing or can maybe used as one of the voltage sense electrodes. The impedance measuringcircuitry processes the voltage sense signal from the voltage senseelectrodes to derive the impedance signal. Further processing of theimpedance signal allows the derivation of signal representingrespiratory activity and/or cardiac blood volume, depending upon thelocation the voltage sense electrodes in the thorax. (See, e.g., U.S.Pat. Nos. 5,190,035 and 6,161,042, assigned to the assignee of thepresent invention and hereby incorporated by reference.) If theimpedance signal is filtered to remove the respiratory component, theresult is a signal that is representative of blood volume in the heartat any point in time, thus allowing the computation of stroke volumeand, when combined with heart rate, computation of cardiac output. Thestroke volume integrated over time (or averaged and multiplied by heartrate) gives the patient's cardiac output. A look-up table or otherfunction may be used to compute what cardiac output is consideredadequate for a given exertion level. Measurement of cardiac output or adetermination of the adequacy of the cardiac output may be used by thedevice to modulate the delivery of RCT and/or ART.

Another means for assessing cardiac function is by determining theautonomic balance of the patient. It is well-known that an increase inthe activity of the sympathetic nervous system may be indicative ofmetabolic stress and the need for increased cardiac output. One means bywhich increased sympathetic activity may be detected is via spectralanalysis of heart rate variability. Heart rate variability refers to thevariability of the time intervals between successive heart beats duringa sinus rhythm and is primarily due to the interaction between thesympathetic and parasympathetic arms of the autonomic nervous system.Spectral analysis of heart rate variability involves decomposing asignal representing successive beat-to-beat intervals into separatecomponents representing the amplitude of the signal at differentoscillation frequencies. It has been found that the amount of signalpower in a low frequency (LF) band ranging from 0.04 to 0.15 Hz isinfluenced by the levels of activity of both the sympathetic andparasympathetic nervous systems, while the amount of signal power in ahigh frequency band (HF) ranging from 0.15 to 0.40 Hz is primarily afunction of parasympathetic activity. The ratio of the signal powers,designated as the LF/HF ratio, is thus a good indicator of the state ofautonomic balance, with a high LF/HF ratio indicating increasedsympathetic activity. An LF/HF ratio which exceeds a specified thresholdvalue may be taken as an indicator that cardiac function is notadequate. A cardiac rhythm management device can be programmed todetermine the LF/HF ratio by analyzing data received from its atrialventricular sensing channels. The intervals between successive atrial orventricular senses, referred to as beat-to-beat or BB intervals, can bemeasured and collected for a period of time or a specified number ofbeats. The resulting series of RR interval values is then stored as adiscrete signal and analyzed to determine its energies in the high andlow frequency bands as described above. Techniques for estimating theLF/HF ratio based upon interval data are described in commonly assignedU.S. patent application Ser. No. 10/436,876 filed May 12, 2003, nowissued as U.S. Pat. No. 7,069,070, and Ser. No. 10/669,170 filed Sep.23, 2003, the disclosures of which are hereby incorporated by reference.

Other means of assessing cardiac function may also be employed tomodulate the delivery of ART and/or RCT. The impedance technique formeasuring cardiac output discussed above may also be used to measureventricular volumes at various stages of the cardiac cycle such asend-diastolic and end-systolic volumes and used to compute parametersreflective of cardiac function such as ejection fraction. Theimplantable device may also be equipped with other sensing modalitiessuch as a pressure transducer. Such a pressure transducer may beattached to an intravascular lead and be appropriately disposed formeasuring diastolic filling pressures and/or systolic pulse pressures.

5. Exemplary Implementations

In an exemplary embodiment of the invention, an implantable device fordelivering cardiac therapy to post-MI patients includes one or morepacing channels for delivering pacing pulses to one or more ventricularsites and a sympathetic inhibition channel for stimulating nerves whichinhibit sympathetic nerve activity. The controller is programmed todeliver remodeling control therapy (RCT) by delivering ventricularpacing in a cardiac resynchronization mode which pre-excites a region ofthe ventricular myocardium so as to mechanically unload that regionduring systole. The cardiac resynchronization therapy may be deliveredas biventricular pacing where one of the ventricles is pre-excitedrelative to the other as determined by a programmed biventricular offsetinterval. Alternatively, in patients suffering from delayed activationof the left ventricle, a left ventricle-only resynchronization pacingmode may be employed. In another embodiment, the pacing therapy may bedelivered as multi-site ventricular pacing where at least one of theventricles is paced at a plurality of sites so as to pre-excite one ormore of the sites relative to the other sites. In any case, theventricular pacing may be delivered in a non-atrial tracking mode wherea ventricular escape interval is defined between ventricular paces, orin an atrial tracking mode where the ventricular paces are deliveredafter a defined atrio-ventricular escape interval following an atrialsense. In a patient who is chronotropically incompetent, an atrialpacing channel may also be provided for pacing the atria, with theventricular pace(s) delivered upon expiration of the atrio-ventricularescape interval following the atrial pace.

The controller is further programmed to delivery anti-remodeling therapy(ART) in conjunction with the RCT by inhibiting sympathetic nerveactivity via the sympathetic inhibition channel. The sympatheticinhibition channel may include a pulse generator for outputting neuralstimulation pulses and a lead incorporating an electrode adapted fordisposition near an arterial baroreceptor or afferent nerve of abaroreflex arc. Stimulation of the baroreflex arc then results ininhibition of sympathetic activity. The electrode of the sympatheticinhibition channel may be intravascularly positioned in a blood vesselor elsewhere proximate to a baroreceptor or afferent nerve such as in apulmonary artery or a cardiac fat pad. In another embodiment, the devicemay further include a parasympathetic stimulation channel, where theanti-remodeling therapy delivered by the controller further includesstimulation of parasympathetic nerve activity, and the parasympatheticstimulation channel includes a pulse generator for outputting neuralstimulation pulses and an electrode for stimulating a parasympatheticnerve. The electrode may be a nerve cuff electrode adapted fordisposition around a parasympathetic nerve or an intravascular electrodefor transvascularly stimulating a parasympathetic nerve adjacent to ablood vessel. As described above, for either the sympathetic inhibitionchannel or the parasympathetic stimulation channel, the electrode andpulse generator may also be incorporated into a satellite unit whichincludes an RF receiver. The implantable device then further comprisesan RF transmitter interfaced to the controller for controlling theoperation of the satellite unit via an RF link.

The device may be programmed to deliver RCT and ART in open-loop fashionwhere the RCT and ART are delivered simultaneously or separately atprogrammed intervals. The RCT and ART may be delivered at a constant ortime-varying intensity, where the intensity of the ART may be adjustedby varying the amplitude, frequency, or duty-cycle of the neuralstimulation pulses, and the intensity of the RCT may be adjusted byvarying one or more parameters which affect the amount of pre-excitationdelivered to the ventricles such as the biventricular offset intervaland the atrio-ventricular escape interval. FIGS. 4A through 4Dillustrate examples of how the level of RCT and ART may be varied withrespect to time. In FIG. 4A, both RCT and ART are deliveredsimultaneously with each type of therapy maintained at a constantintensity. In FIG. 4B, both RCT and ART are delivered at a constantintensity, but ART starts at a time T₁ while RCT starts at a time T₂. InFIGS. 4C and 4D, the intensity of each type of therapy is modulated withrespect to time. FIG. 4C shows the intensity of both the RCT and ARTincreasing with respect to time, while FIG. 4D shows the intensity ofthe RCT increasing while the intensity of the ART decreases. Therelative intensities of sympathetic inhibition and parasympatheticstimulation may also be separately modulated.

In another embodiment, the device is programmed to deliver RCT and ARTin closed-loop fashion, where the intensities of RCT and ART aremodulated in accordance with an assessment of cardiac function performedby the controller. The device may also separately modulate theintensities of parasympathetic stimulation and sympathetic inhibitionwhich are delivered as part of the ART in accordance with the assessmentof cardiac function. Cardiac function may be assessed by the deviceusing several different modalities, either alone or in combination. Inone embodiment, the device incorporates a sensor for measuring cardiacoutput, and the controller is programmed to modulate the delivery of RCTand ART in accordance with the measured cardiac output. As describedabove, such a cardiac output sensor may be a trans-throracic impedancemeasuring circuit. Another means for assessing cardiac function is anarterial blood pressure sensor, where the controller is programmed tomodulate the delivery of RCT and ART in accordance with the measuredblood pressure. The blood pressure sensor may take the form of apressure transducer and lead adapted for disposition within an artery.Alternatively, a measure of the patient's respiratory activity taken bya minute ventilation sensor may be used as a surrogate for bloodpressure. Cardiac function may also be assessed by measuring thepatient's exertion level (e.g., using either a minute ventilation sensoror an accelerometer) together with a measure of cardiac output and/orblood pressure, where the controller is then programmed to modulate thedelivery of RCT and ART in accordance with the combined measurements.

In another embodiment, the cardiac function assessment includes anassessment of the patient's autonomic balance. Autonomic balance may beassessed directly with a sensing channel for measuring electricalactivity in sympathetic and parasympathetic nerves with appropriatelypositioned sensing electrodes, or if the patient is chronotropicallycompetent, by measuring the intrinsic heart rate. As described above,measuring heart rate variability provides one means for assessingautonomic balance. Thus, the device may include circuitry for measuringand collecting time intervals between successive intrinsic beats,referred to as a BB interval, where the BB interval may be an intervalbetween successive atrial or ventricular senses. The device stores thecollected intervals as a discrete BB interval signal, filters the BBinterval signal into defined high and low frequency bands, anddetermines the signal power of the BB interval signal in each of the lowand high frequency bands, referred to LF and HF, respectively. Thedevice then computes an LF/HF ratio and assesses autonomic balance bycomparing the LF/HF ratio to a specified threshold value.

In certain embodiments, data gathered by the device in performing theassessment of cardiac function performed is transmitted to a remotemonitor via an RF telemetry link. The remote monitor may record the datafor later analysis by a clinician and/or transmit it to another locationover a network such as the internet. In response to networkcommunications, the remote monitor may also program the implantabledevice via the RF telemetry link in order to modify the delivery of RCTand ART.

Although the invention has been described in conjunction with theforegoing specific embodiments, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Such alternatives, variations, and modifications are intended to fallwithin the scope of the following appended claims.

1. An implantable device for delivering cardiac therapy to a patient,comprising: one or more pulse generators for generating pacing pulsesand neural stimulation pulses; a parasympathetic stimulation channel forstimulating parasympathetic nerve activity by delivering neuralstimulation pulses; a sensor for measuring cardiac output; a controllerfor controlling the delivery of pacing pulses to one or more ventricularsites during a cardiac cycle in accordance with a programmed pacingmode; wherein the controller is programmed to deliver remodeling controltherapy (RCT) by controllably delivering ventricular pacing in a mannerwhich pre-excites a region of the ventricular myocardium so as tomechanically unload that region during systole; wherein the controlleris further programmed to deliver anti-remodeling therapy (ART) bycontrolling stimulation of parasympathetic nerve activity via theparasympathetic stimulation channel; wherein the controller isprogrammed to perform an assessment of cardiac function and to modulatethe delivery of RCT and ART in accordance with the assessment of cardiacfunction, wherein the assessment of cardiac function includes themeasurement of cardiac output; and, wherein ART is modulated in responseto the assessment of cardiac function by varying the amplitude of theneural stimulation pulses.
 2. The device of claim 1 further comprising aneural inhibition channel for inhibiting sympathetic nerve activity andwherein the anti-remodeling therapy delivered by the controller furtherincludes inhibition of sympathetic nerve activity.
 3. The device ofclaim 1 wherein the parasympathetic stimulation channel includes a nervecuff electrode adapted for disposition around a parasympathetic nerve.4. The device of claim 1 wherein the parasympathetic stimulation channelincludes an electrode adapted for intravascular disposition in order totransvascularly stimulate a parasympathetic nerve adjacent a bloodvessel.
 5. The device of claim 1 wherein the cardiac output sensor is atrans-thoracic impedance measuring circuit.
 6. The device of claim 1further comprising an arterial blood pressure sensor and wherein thecardiac function assessment further includes the measured bloodpressure.
 7. The device of claim 1 further comprising an exertion levelsensor for measuring the patient's exertion level, and wherein thecardiac function assessment further includes the measured exertionlevel.
 8. The device of claim 1 further comprising a sensing channel fordetecting cardiac activity; circuitry for measuring heart ratevariability based on the sensed cardiac activity and for assessing thepatient's autonomic balance based on the measured heart ratevariability; and wherein the cardiac function assessment furtherincludes the assessment of the patient's autonomic balance based uponheart rate variability.
 9. The device of claim 1 wherein RCT ismodulated in response to the assessment of cardiac function by varyingthe extent of pre-excitation provided to a ventricular pacing site. 10.The device of claim 1 wherein ART is further modulated in response tothe assessment of cardiac function by varying the amplitude, frequency,or duty cycle of parasympathetic stimulation pulses.
 11. The device ofclaim 1 wherein the controller is programmed to deliver RCT asbiventricular pacing so as to pre-excite one of the ventricles relativeto the other.
 12. The device of claim 1 wherein the controller isprogrammed to deliver RCT as multi-site ventricular pacing where atleast one of the ventricles is paced at a plurality of sites so as topre-excite one or more of the sites relative to the other sites.
 13. Thedevice of claim 1 wherein the controller is programmed to deliver RCT asleft ventricle-only pacing which pre-excites the left ventricle relativeto the right ventricle during systole.
 14. A method for operating acardiac device to deliver cardiac therapy to a patient, comprising:delivering remodeling control therapy (RCT) by controllably deliveringventricular pacing through one or more pacing channels in accordancewith a programmed mode in a manner which pre-excites a region of theventricular myocardium so as to mechanically unload that region duringsystole; delivering anti-remodeling therapy (ART) by controllingstimulation of parasympathetic nerve activity via a parasympatheticstimulation channel; measuring cardiac output; and, performing anassessment of cardiac function and modulating the delivery RCT and ARTin accordance with the assessment of cardiac function, wherein theassessment of cardiac function includes the measured cardiac output andwherein ART is modulated by varying an amplitude of the parasympatheticnerve stimulation.
 15. The method of claim 14 further comprisingmeasuring arterial blood pressure and wherein the assessment of cardiacfunction further includes the measured arterial blood pressure.
 16. Themethod of claim 14 further comprising measuring exertion level whereinthe assessment of cardiac function further includes the measuredexertion level.
 17. The method of claim 14 further comprising measuringheart rate variability, assessing the patient's autonomic balance basedupon the measured heart rate variability, and wherein the assessment ofcardiac function further includes the assessment of the patient'sautonomic balance based upon heart rate variability.
 18. The method ofclaim 14 wherein the anti-remodeling therapy further includes inhibitionof sympathetic nerve activity.